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Prodrug Formulations Create Sustained Release Antiretrovirals

前药制剂可产生持续释放的抗逆转录病毒药物

基本信息

批准号：
10652403
负责人：
Benson Edagwa
金额：
$ 75.71万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10652403
关键词：
AIDS prevention Acceleration Adherence Adverse effects Adverse event Animal Model Animals Anti-Retroviral Agents Area Binding Proteins Biological Assay Biological Availability Biological Testing Blood CD34 gene CD4 Positive T Lymphocytes Cell Count Cell model Cells Central Nervous System Chemistry Collaborations Combined Modality Therapy Critiques Data Data Set Dendritic Cells Development Dose Drug Combinations Drug Formulations Drug Interactions Drug Kinetics Drug Targeting Drug Transport Drug resistance Drug toxicity Effectiveness Endosomes Excipients Excretory function FDA approved Female Formulation Frequencies Funding Genitourinary system Goals Good Manufacturing Process Guidelines Gut associated lymphoid tissue HIV HIV-1 Half-Life Human Hydrolysis Immunologics Immunologist Immunology Inbred BALB C Mice Individual Infection Injections Integrase Integrase Inhibitors Intramuscular Injections Laboratories Lamivudine Lipids Lymphoid Macrophage Measures Medicine Metabolic Metabolism Monitor Mononuclear Mus Muscle Nucleosides Outcome Pathway interactions Phagocytes Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Plasma Polymers Prevention Prevention strategy Prodrugs Production Property Publishing RNA-Directed DNA Polymerase Regimen Research Reverse Transcriptase Inhibitors Safety Scheme Sex Differences Site Sprague-Dawley Rats Suspensions T-Lymphocyte Tenofovir Test Result Testing Therapeutic Time Tissues Toxic effect Toxicology Translating Treatment Protocols Viral Viral Load result Viral reservoir Virus Virus Diseases abacavir antiretroviral therapy aqueous biomaterial compatibility chemical stability clinically relevant cytotoxicity design drug distribution drug efficacy emtricitabine expectation experimental study humanized mouse improved inhibitor lipophilicity lymphoid organ male manufacture monocyte mouse model nano nanocrystal nanomedicine particle pharmacokinetics and pharmacodynamics pre-exposure prophylaxis product development reconstitution response scale up screening side effect success surfactant therapy outcome tool trafficking transmission process treatment strategy uptake virology

项目摘要

Abstract This proposal seeks funds to translate existing antiretroviral drugs (ARVs) into scalable long acting medicines. A step-wise approach is offered with defined “go no go” criteria. The first is conversion of nucleoside reverse transcriptase and an integrase inhibitor(s) into lipophilic prodrug nanocrystals. These conversions are designed for simple, safe and scalable productions under current good manufacturing practices. Following the production of ARV nanocrystals, the second step will optimize CD4+ T cell uptake while sustaining drug depots in macrophages. ARV release from prodrugs will occur by controlled hydrolysis enabling sustained antiretroviral potency. The third will facilitate distribution of prodrug nanocrystals into lymphoid, gut associated lymphoid tissue, genitourinary and central nervous system tissues. The fourth, will complete tests designed to limit off target toxicity (S Cohen) by screening pro-, native- and nanocrystal- drug formulations in cell and tissue assays. These extended toxicology tests will serves to investigate any or no adverse events that follow increased ARV levels in cells and tissues. Our goal is the production of safe well-tolerated long acting slow effective release antiretroviral therapies with “putative” dosing intervals of up to once every six months. The design will offer maximal effectiveness for pre-exposure prophylaxis and treatment regimens. The specific aims are supported by extensive published data sets. To accomplish the proposed research, a partnership was made between a medicinal and polymer chemist (B Edagwa) and a virologist, cell biologist, and immunologist (H Gendelman). This collaboration will accelerate transformation of short- to long-acting ARVs. Biological testing will follow product development in cell and animal models. Formulation safety will be realized by continuous testing of replicate short-acting native ARV formulations in good laboratory and current good manufacturing practice facilities. The pathway for ARV nanocrystal development will move forward by sequential Go No Go criteria. Drug choices, formulation stability, drug combinations, tissue and cell targeting, toxicology, pharmacokinetics (PK), and pharmacodynamics (PD) profiles follow the action plan. Several have “reached” drug manufacture. The outcome of these experiments can reduce drug toxicities, improve regimen adherence, and provide enhanced viral prevention into tissue reservoirs. The research builds on an already strong track record in cell-targeted nanomedicines. Antiretroviral responses and endosomal trafficking will be tested. PK and PD mouse screens (S Gorantla) will validate the findings. Overall, our long-term goal is to transform existing antiretroviral treatment regimens into long acting therapies.

摘要该提案寻求资金，将现有的抗逆转录病毒药物转化为可扩展的长效药物。提供了一种逐步的方法，并规定了“去不去”的标准。第一种是核苷反向转化在一个实施方案中，所述方法包括将一种或多种转录酶和一种或多种整合酶抑制剂转化成亲脂性前药纳米晶体。这些转换旨在在当前良好的生产规范下进行简单、安全和可扩展的生产。后生产ARV纳米晶体，第二步将优化CD4+ T细胞摄取，同时维持药物巨噬细胞中的储存库。ARV从前药的释放将通过控制水解发生，抗逆转录病毒效力。第三个将促进前药纳米晶体分布到淋巴，肠道相关的淋巴组织、泌尿生殖系统和中枢神经系统组织。第四，将完成旨在通过在细胞中筛选前体、天然和非天然药物制剂来限制靶向毒性（S Cohen），组织测定。这些扩展的毒理学试验将用于调查任何或没有不良事件，增加细胞和组织中的抗逆转录病毒水平。我们的目标是生产安全、耐受性好、长效缓有效释放抗逆转录病毒疗法，“假定”给药间隔高达每六个月一次。的设计将为暴露前预防和治疗方案提供最大的有效性。具体目标得到了广泛的已发表数据集的支持。为了完成拟议的研究，一位药物和聚合物化学家（B Edagwa）和一位病毒学家、细胞生物学家和免疫学家之间的对话（H Gendelman）.这一合作将加速短效抗逆转录病毒药物向长效抗逆转录病毒药物的转变。生物测试将在产品开发之后在细胞和动物模型中进行。制剂安全性将通过以下方式实现在良好实验室和当前良好环境中连续测试重复短效天然抗逆转录病毒制剂生产实践设施。抗逆转录病毒药物研发的道路将向前推进，连续的“去不去”标准。药物选择、制剂稳定性、药物组合、组织和细胞靶向，毒理学、药代动力学（PK）和药效学（PD）特征遵循行动计划。几个已经 “制造”毒品。这些实验的结果可以降低药物毒性，改善治疗方案，粘附，并提供增强的病毒进入组织储库的预防。这项研究建立在一个已经在细胞靶向纳米医学方面有着良好的记录。抗逆转录病毒反应和内体运输将是测试. PK和PD小鼠筛选（S Gorantla）将验证结果。总的来说，我们的长期目标是将现有的抗逆转录病毒治疗方案转变为长效疗法。